Genetic discovery could fuel new treatment research for liver disease

A team of researchers with Geisinger Health System and the Regeneron Genetics Center recently published their research in the New England Journal of Medicine detailing how DNA samples coupled with genetic material from liver tissue peeled back the curtain on a mutation they hope will fuel new treatment for an increasingly common, deadly disease.

Chronic liver disease and cirrhosis accounted for more than 38,000 deaths in 2014, a statistic driven by rising obesity, which has a heavy hand in fat deposits on the liver.

While the gene mutations don’t stave off fat deposits, they prevent the progression to inflammation and fibrosis, or scar tissue buildup, that can ultimately lead to liver failure and death.

“There’s a real need to have medical ways to treat this disease,” said David Carey, Ph.D., chairman of Geisinger’s Department of Molecular and Functional Genomics and a co-author of the report. “Right now, the best option that’s available is to recommend weight loss but that doesn’t work very well for everybody.”

The experiment tapped genetic data from nearly 47,000 MyCode Community Health Initiative participants. So far, Geisinger recruited more than 190,000 people in Northeast Pennsylvania and the surrounding region to donate their DNA for research.

The lynch pin, however, was connecting the data with genetic liver material that surgeons capture during bariatric surgery procedures and store in a tissue bank.

“This was the first way that it was really linked to the progression of this particular disease,” Carey said. “The human genetics, and our ability to link the genetic variation to this very detailed clinical information that we had on these patients was really the key to unlocking this secret.”

The mutation works by not working.

Loss of function in the gene, they discovered, significantly reduces the likelihood of liver disease, and that’s a good thing.

Drug companies have an easier time developing medicine that cripples the gene rather than make it do something else.

“We kind of got lucky,” said Tooraj Mirshahi, Ph.D., a Geisinger associate professor in the Department of Functional and Molecular Genomics. “Mimicking the loss of functionality is something that the drug companies could go after to develop a drug that henceforth would slow the progression of the disease.”

Researchers found the mutation led to a 73 percent lower risk of alcoholic cirrhosis and 49 percent lower risk of nonalcoholic cirrhosis.

Although the benefits to heavy drinkers appear greater, the study group included far more people at risk because they are overweight — 190 patients in the alcoholic liver disease group and nearly 1,900 in the nonalcoholic liver disease group.

“It is 10 times as many of them who have the nonalcoholic version, so that really is the big public health issue,” Mirshahi said.

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